EP2252575A1

EP2252575A1 - 2-amino-2-phenylalkanol derivatives, preparation thereof and pharmaceutical compositions containing same

Info

Publication number: EP2252575A1
Application number: EP09720924A
Authority: EP
Inventors: Alexis Denis; Jean Pachot; Christophe Dini
Original assignee: Oroxcell
Current assignee: Oroxcell
Priority date: 2008-01-31
Filing date: 2009-01-30
Publication date: 2010-11-24
Anticipated expiration: 2029-01-30
Also published as: US20090197924A1; MA32125B1; AU2009224558B2; PT2252575E; KR20110103834A; CA2712489A1; UA101013C2; AU2009224558A1; MX2010008430A; IL206936A; IL206936A0; CN101932552B; PL2252575T3; ZA201005316B; CN101932552A; GEP20125563B; RU2486174C2; FR2927076B1; DK2252575T3; ES2400080T3

Abstract

Esters derived from 2-amino-2-phenylalkanol of general formula (I) in which: R₁ is H, straight or branched C1 to C4 alkyl, straight or branched C2 to C4 alkyl substituted by OH, alkoxy, alkylthio, acyloxy, NH₂, alkylamino, dialkylamino, alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, R₂ is a -CO-R radical in which R is H, alkyl, aryl, heterocyclyl, benzyl or heterocyclylmethyl, or else R₂ is a -CO-Y-R₄ radical for which Y is -O-, -S-, -NH-, or -Nalk- for which alk is straight or branched (C1 to C4) alkyl, and R₄ is alkyl, aryl, aralkyl or heterocyclylalkyl, which may be substituted by one or more halogen atoms or OH radicals, straight or branched (C1 to C4) alkyl radicals, or straight or branched (C1 to C4) alkoxy, alkylthio, acylaminoalkylthio, alkoxycarbonyl or acylamino radicals, or oxo radicals, or which may be substituted by R₅COO- in which R₅ is an alkyl optionally substituted by benzyloxycarbonylamino, acylamino or by the residue of an amino acid, or represents a heterocycle, or else R₂ is a (C2 to C4) alkyl substituted by OH, alkoxy, alkylthio, acyloxy, NH₂, alkylamino, dialkylamino optionally forming, with the nitrogen atom to which they are attached, a 5-or 6-membered heterocycle optionally bearing another heteroatom (O or N), or substituted by alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, it being understood that said straight or branched substituted alkyl radical comprises at least C2 between >N-R₂ and the substituent; and R₃ is a straight or branched (C1 to C4) alkyl unless specifically mentioned, alkyl or acyl are straight or branched (C1 to C7), in their R or S forms or mixtures thereof, and also the pharmaceutically acceptable salts thereof when they exist.

Description

2-AMINO-2-PHENYL-ALKANOL DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to derivatives of 2-amino-2-phenyl-alkanol variously substituted which are particularly interesting especially for their analgesic action. The present invention also relates to the preparation of these derivatives as well as the pharmaceutical compositions containing them.

In international application WO 99/01417 has been described (S) 3,4,5-trimethoxy benzoate 2-methylamino-2-phenyl-n.butyl and its use in the treatment of chronic pain. In the European application EP 1 110 549 the use of trimebutine [3,4-trimethyloxy-2-methylamino-2-phenyl] butyl] maleate or its stereoisomers in the treatment of inflammatory disorders and pain have been described.

British Patent Application GB 1 434 826 has described aminoalcohol esters of structure:

in which R1 to R3 may especially be a hydrogen atom, R4 may be an alkyl radical, R7 may be aryl optionally substituted with 1 to 3 alkoxy radicals and R5 and R6 represent a hydrogen atom, an alkyl or aralkyl radical or form together with the nitrogen atom to which they are attached a heterocycle. The products are useful as anti-spasm agents. The British application also describes carbamates for which R ₇ has the structure -NH-R _"7. The aryl carbamates thus constituted are endowed with analgesic and anti-inflammatory activity. However changes in the amino were quite limited and could not not lead to powerful painkillers.

It has now been found that esters derived from 2-amino-2-phenylalkanol of general formula:

in which : R 1 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain, an alkyl radical containing 2 to 4 C in straight or branched chain substituted by hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino, alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, R ₂ is a radical -CO-R wherein R is a hydrogen atom, an alkyl, aryl, heterocyclyl, benzyl or heterocyclyl radical, a -CO-YR ₄ for which Y is a heteroatom selected from -O-, -S-, -NH-, -NaIk- for which alk is a straight or branched alkyl radical containing 1 to 4C, and R ₄ is selected from alkyl, aryl, aralkyl or heterocyclylalkyl, which may be substituted by one or more halogen atoms or hydroxy, alkyl radicals containing from 1 to 4C in straight or branched chain, alkoxy, alkylthio, acylaminoalkylthio, alkoxycarbonyl or acylamino, the alkyl radicals of which contain 1 to 4C in the form of straight or branched chain, or oxo, or which may be substituted by a radical R ₅ COO- in which R ₅ is an alkyl radical optionally substituted by benzyloxycarbonylamino, acylamino or the residue of an amino acid, or represents a heterocyclyl radical, or

R ₂ is an alkyl radical containing 2 to 4C substituted with hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino, the alkyl parts of which can form, with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle optionally carrying another heteroatom selected from oxygen or nitrogen, or substituted by alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, it being understood that said substituted alkyl radical is straight or branched chain and has at least 2 carbon atoms between nitrogen atom carrying R ₂ and the substituent;

R ₃ is an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, in their R or S forms or mixtures thereof, and their pharmaceutically acceptable salts, when they exist, exhibit a particularly interesting activity as analgesics, in particular in the treatment of chronic pain.

It is understood that, except where otherwise stated, the radicals or the alkyl or acyl radicals are straight or branched and contain 1 to 7 carbon atoms, in particular the acyl radicals may be acetyl radicals. The aryl or aralkyl radicals can be mono or bicyclic radicals, comprising 6 to 10 members, for example phenyl, naphthyl, benzyl, phenethyl or naphthylalkyl.

It is understood that the heterocyclyl radicals may be mono- or bicyclic aromatic or non-aromatic radicals, comprising 5 to 10 members and containing 1 to 4 heteroatoms chosen from oxygen, nitrogen or sulfur. In particular, they may be chosen from thienyl, furyl, pyrrolyl, pyrrolidinylpiperidylpyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, dioxolyl, imidazolyl, imidazolinyl, pyrazolyl and tetrazolyl radicals. pyrannyl, tetrahydropyranyl, tetrahydrofuran, oxazolyl, thiazolyl, thiazinyl, morpholinyl, thiomorpholinyl, indolyl, indolizinyl, quinolyl, naphthyridinyl.

It is understood that the amino acids mentioned above may be chosen in particular from glycine, alanine, leucine, isoleucine, proline, valine, phenylalanine in series L or D and that these groups are protected prior to the synthesis reactions, in the form of amides or carbamates; the protection and release of the protective radicals is carried out according to the methods described by T. W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th Edition ISBN 978-0-471-69754-1, December 2006.

The halogen atoms are selected from chlorine, fluorine, bromine and iodine. According to a preferred embodiment of the invention, the alkyl or acyl radicals are straight or branched and contain 1 to 4 carbon atoms.

According to the invention, the esters derived from 2-amino-2-phenyl-alkanol of general formula (I) are prepared by the action of a derivative of general formula:

wherein Z is a halogen atom, a hydroxy radical or the residue of a reactive ester, on the 2-amino-2-phenylalkanol derivative of the general formula:

in which R 1 and R ₃ are as previously defined and R ' ₂ is a hydrogen atom or is defined as R ₂ above, followed if appropriate, when one of R' ₂ or R 1 is the hydrogen atom of the substitution of the obtained 2-amino-2-phenylalkanol derived ester amine of general formula:

in which R 1, R ' ₂ and R ₃ are defined as above, Or, when R ' ₂ is H, and if it is desired to obtain derivatives for which R ₂ is -CO-R, by the action of a reactive derivative of the acid of general formula

R-COOH (V) in which R is defined as above, or • when R ' ₂ is H, and if it is desired to obtain derivatives for which R ₂ is -CO-YR ₄ , Y being O, S, NH or NaIk or, by action of phosgene, followed by the reaction with alcohol, thiol or amine of general formula:

R ₄ -YH (VI) in which R ₄ is an optionally substituted alkyl radical and, where appropriate, the alterable functional groups in the reaction are protected beforehand, or an aryl, aralkyl or heterocyclylalkyl radical, and Y is the oxygen atom or sulfur, or an NH or NaIk radical or, by action of the halide of general formula: R ₄ -Y-COHaI (VII) wherein R ₄ is defined as above, preferably aryl or branched alkyl, Y is the an oxygen or sulfur atom and HaI is a halogen atom, preferably chlorine, or, when it is desired to obtain a radical R ₄ bearing the -C (alk) -O-CO-R ₅ substitution, defined below, for which alk is an alkyl radical containing 1 to 6 carbon atoms in straight or branched chain and R ₅ is defined as in the general formula (I), by the action of chloroalkylchloroformate, followed by the reaction of the product obtained with an alkaline salt of the corresponding acid

R ₅ COOH, for example the sodium salt, potassium salt or cesium salt R ₅ COOCs, or the silver salt or a quaternary ammonium salt (such as for example the tert-butyl ammonium salt), this acid.

Or, when R ' ₂ is H, and if it is desired to obtain derivatives for which R ₂ is substituted alkyl, or when a derivative of general formula (IV) has been obtained for which

R 1 is a hydrogen atom and R ' ₂ is defined as R ₂ , and if it is desired to obtain a product of general formula (I) for which R 1 is optionally substituted alkyl, by acylation with an acid halide or a reactive ester of structure:

R ₂ -CO-Z (VIIIa) or R ₁ -CO-Z (VIIIb) wherein R 1 or R ₂ are defined as above and Z is a halogen atom or the remainder of a reactive ester, followed by reduction of the amide formed to an amine.

Or else, when a derivative of general formula (IV) has been obtained for which R 1 is a hydrogen atom and R ' ₂ is defined as R ₂ , and if it is desired to obtain a product of general formula ( I) for which R 1 is alkyl, by the action of a halogen derivative of formula

R ₁ -X (IX) wherein R 1 is an alkyl radical and X is a halogen atom or a sulfonic radical in the presence of a base.

The product of general formula (II) may be a reactive derivative of 3,4,5-trimethoxybenzoic acid such as an acid halide or a reactive ester.

The reaction of the 2-amino-2-phenylalkanol derivative of general formula (III) is preferably carried out by means of a derivative for which R ' ₂ is the hydrogen atom.

When the product of general formula (II) is a reactive derivative of 3,4,5-trimethoxybenzoic acid such as the acid halide or a reactive ester, the reaction of the derivative of general formula (II) on the derivative 2-amino-2-phenylalkanol of general formula (III) is advantageously carried out in the presence of a nitrogenous base such as for example triethylamine, dimethylaminopyridine, diisopropylethylamine in the case of the acid halide of formula (II) and the reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), at a temperature of between 0 and 70 ° C., preferably operating under nitrogen. And in the case of a reactive ester of formula (II), in the presence of sodium methoxide in an organic solvent such as toluene in the presence of an alcohol such as methanol or ethanol, at a temperature between 25 and 150 ° C. When Z is a halogen atom, it is advantageously chosen from chlorine or bromine.

When the product of general formula (II) is 3,4,5-trimethoxybenzoic acid, the reaction is generally carried out in the presence of a carbodiimide, in a halogenated solvent (dichloromethane, dichloroethane, chloroform for example), at a temperature of temperature between 0 and 70 ° C. It is understood that when it is desired to obtain a derivative of general formula (IV) of R or S form, a 2-amino-2-phenylalkanol derivative of general formula (III) of R or S form is reacted. It is also understood that the derivatives of general formula (IV) of R or S form lead to derivatives of general formula (I) of R or S form.

The substitution of the amine of the derivative of general formula (IV) by the action of a reactive derivative of the acid of general formula (V) is advantageously carried out by means of the halide acid or ester, especially reactive ester, preferably in the presence of a condensing agent such as a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular). The reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform, for example), at a temperature of between 0 and 70 ^° C. When it is desired to obtain the derivative for which R ₂ is formyl, it is advantageous to operate by an ester action, the use of a solvent may be unnecessary.

The reaction of the alcohol or thiol of general formula (VI) is carried out after the action of phosgene on the amine of the derivative of general formula (IV), (in the form of a solution in an aromatic solvent such as, for example, toluene), in an organic solvent such as a halogenated solvent (for example a chlorinated solvent such as dichloromethane, dichloroethane or chloroform) in the presence of a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular) at a temperature of between 0 and 25 ° C. . The reaction of the alcohol or thiol of general formula (VI) is carried out by adding the derivative of general formula (VI) in the presence of a tertiary amine as mentioned above, at a temperature between 0 and 70 ° C. in a halogenated solvent (dichloromethane, dichloroethane, chloroform, for example). Preferably one operates under nitrogen. It is understood that when substituents may be altered during the reaction, the latter are previously protected. The protection and the release of the protective radicals is carried out according to the methods described by T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 4th Edition ISBN 978-0-471-69754-1, December 2006.

The reaction of the derivative of general formula (VII) with the amine of the derivative of general formula (IV) is carried out in the presence of a condensing agent such as a tertiary amine (triethylamine, diisopropylethylamine, dimethylaminopyridine in particular). The reaction is generally carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example) or tetrahydrofuran, at a temperature between 0 and 70 ° C. Preferably one operates under nitrogen.

When it is desired to obtain a product for which the radical R ₄ bears the substitution -C (alk) -O-CO-R ₅ , the reaction of chloroalkylchloroformate with the product of general formula (IV) is carried out, the reaction being carried out is carried out in an organic solvent such as a chlorinated solvent (dichloromethane, dichloroethane for example), or as an ether (tetrahydrofuran for example), at a temperature of between -10 and 50 ^° C. It is followed by the reaction of the product obtained with a alkali salt of the corresponding acid R ₅ COOH, for example the sodium salt, potassium salt or cesium salt, the silver salt, or a quaternary ammonium salt, in an organic solvent such as an amide as dimethylformamide, a chlorinated solvent (for example dichloromethane), an ester (ethyl acetate for example), an aromatic hydrocarbon (toluene for example), a nitrile (acetonitrile for example), a ketone (acetone, methyl ethyl ketone for example), in the presence or absence of sodium iodide, at a temperature between 0 and 60 ° C.

When it is desired to obtain a derivative of general formula (I) for which R 2 is substituted alkyl or for which R 1 is optionally substituted alkyl, the alkylation reaction of the amine of the derivative of general formula (IV) takes place in a halogenated solvent (dichloromethane, dichloroethane for example) or in an ether (tetrahydrofuran), at a temperature between 0 and 70 ° C. If appropriate, the reactive ester may be prepared using hydroxybenzotriazole. The reduction is carried out in the presence of borane in tetrahydrofuran, at a temperature between 0 and 70 ° C. The reaction of the product of formula (IX) with the 2-amino-2-phenyl-alkanol derivative of general formula (IV) is carried out by means of a halogenated derivative for which the halogen is chosen from chlorine, bromine or iodine or by means of a sulphonic derivative such as tosylate, mesylate or triflate, in the presence of a base such as an alkaline carbonate (NaHCO ₃ or KHCO ₃ for example). The 3,4,5-trimethoxybenzoic acid derivatives of general formula (II) can be prepared according to the usual methods for converting carboxylic acids into their reactive derivatives, which do not affect the rest of the molecule.

The derivatives of general formula (III) can be prepared according to the method described in patent applications FR 2 765 218 or EP 510 168, or by analogy with the method described in these applications.

The halogenated derivatives of general formula (VII) can be prepared by the action of phosgene on the alcohol or the corresponding thiol of general formula (VI). It operates under conditions similar to the conditions described above for the action of phosgene on the amine of the derivative of general formula (IV). It is understood that when it is desired to obtain a product of general formula (I) in S or R form, a 2-amino-2-phenylalkanol derivative of general formula (III) of form S or R is reacted.

The 2-amino-2-phenyl alkanol derivatives of general formula (III) of S or R form may be prepared according to the method described in European Patent EP 510,168 or by separation according to the usual methods of separation of enantiomers which do not affect not the rest of the molecule.

When they exist, the pharmaceutically acceptable salts may be acid addition salts. In particular, salts with mineral acids such as, for example, hydrochlorides, hydrobromides, sulphates, phosphates or addition salts with organic acids such as acetates, maleates, fumarates, tartrates, citrates.

The derivatives of general formula (I) can be purified according to the usual methods, in particular by chromatography or by crystallization. The derivatives of general formula (I) are particularly interesting because of their powerful analgesic activity, especially in chronic pain.

Their activity has been demonstrated in vitro in the sodium channel inhibition test by application of the method of GB Brown, ³ H-batrachotoxinin-A benzoate binding to voltage sensitive sodium channels: inhibition by the channel blockers tetrodotoxin saxitoxin, J. Neurosci., 6, 2064 (1986). In vitro in this test, the products according to the invention showed activities between 25 and 90% inhibition for concentrations of 3.2 (M).

Moreover, in vivo their activity has been demonstrated in rats in the test of formalin-induced short-phase and long-phase adapted pain of the method of Wheeler-Aceto et al., Psychopharmacology, 104, 35-44 (1991). In this method, the product of Example 4 was active at the dose of 39.3 mg / kg subcutaneously in the short and long phase. In vivo activity was also demonstrated in the abdominal pain test, by irritation and distension of the colon, in the rat according to the method adapted from the method described by Langlois et al., Eur. J. Pharmacol., 324, 21-217 (1997). In this test, the product of Example 4 was active in rats, starting at 13.1 mg / kg and at doses of 26.2 mg / kg subcutaneously.

In addition, it has been demonstrated, after i.v. injection in the rat, that the half-life time of some products according to the present invention are particularly high.

Finally, the products according to the invention do not exhibit toxicity. Indeed, in the mouse intraperitoneally at doses of 26.2 mg / kg in 7 repeated administrations in 2 days and in the oral rat at 39.3 mg / kg, no mortality and no sign of abnormal behavior. 'have been observed.

Of particular interest are the products of general formula (I) below called (Ia) for which R 1 and R ₃ are defined as above and R ₂ in -NR ₁ R ₂ is a radical -CO-OR ₄ for which R 4 has a structure: -C (alk) -O-CO-R ₅ (X) alk being an alkyl radical containing 1 to 6 carbon atoms in straight or branched chain and R ₅ is defined as in general formula (I), or else called after (Ia ') for which R ₃ is defined as above and in -NR] R ₂ , R) is a hydrogen atom and R ₂ is a radical -CO-R as defined above. Among the products of general formula (Ia) and (Ia ') are more particularly preferred the products of general formula (Ia) for which R 1 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms (especially methyl ) or a 2-methoxyethyl radical. Also preferred are the products of general formula (I), hereinafter referred to as (Ib), for which R 1 and R ₃ are defined as above and R ₂ in -NR ₁ R ₂ is a substituted alkyl radical as defined previously for R ₂ in the general formula (I).

The following examples illustrate the present invention.

In the examples which follow, the abbreviations employed have the following meanings: DMF dimethylformamide DMSO dimethylsulfoxide THF tetrahydrofuran DIPEA ΛyV-diisopropylethylamine TLC Thin Layer Chromatography Example 1 ORC012

0.300 g (0.8 mmol, 1 eq) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate and 0.442 g (2.4 mmol, 3 eq) of nicotinoyl hydrochloride are placed under nitrogen and then suspended in 3ml of 1, 2-dichloroethane dry. 0.4 ml (2.4 mmol, 3 eq) of N, N-diisopropylethylamine are then added. Stirring is maintained for 20 hours at room temperature.

The reaction mixture is treated with 6 ml of saturated NaHCO ₃ and then extracted with 12 ml of dichloromethane. The organic phase is washed again with 6 ml saturated NaHCO ₃ and then dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residue obtained is purified by flash chromatography on silica gel (gradient ethyl acetate / cyclohexane 3: 7 to 6: 4, v / v) to give 0.189 g (46%) of the expected product 3,4,5-trimethoxybenzoate (S) 2- (methyl-3-pyridylcarbonylamino) -2-phenyl-n-butyl as a white foam.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.93 (t, J = 7.6Hz, 3H, CH _3); 2.27 (m, 1H, CH ₂ diastereotope); 2.52 (m, 1H, CH ₂ diastereotope); 2.91 (s, 3H, NCH ₃ ); 3.77 (s, 6H, 2xOCH ₃ ); 3.82 (s, 3H, OCH ₃ ); 5.03 (d,

J = 1.5Hz, 1H, OCH ₂ ); 5.24 (d, J = 1, 5Hz, 1H, OCH ₂ ); 7.10-7.40 (m, 8H, ArH); 7.73 (d, J = 7.8 Hz, 1H, ArH); 8.57 (d, J = 4.9 Hz, 1H, ArH); 8.66 (m, 1H, ArH). LC-MS (ES): m / z = 479 (M + H) ⁺ . R _f (SiO ₂ , dichloromethane / methanol 98: 2): 0.36.

(S) 2-Methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate can be prepared according to the method described in applications FR 2765218 and EP 0510168. Example 2 Synthesis of ORCOl 1:

ORC002 ORC011

Step 1 :

1.17 g (2.83 mmol, 1 eq) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate is placed under nitrogen and then solubilized in 1 ml of 1,2 dichloroethane. 0.77 ml (8.50 mmol, 3 eq) of chloromethyl chloroformate are then slowly added dropwise. The mixture is stirred for 6 hours at room temperature and then the reaction mixture is treated with saturated NaHCO _{3 (} 10 ml) and then extracted with 20 ml of dichloromethane. The organic phase is washed again with 10 ml saturated NaHCO ₃ , dried over Na ₂ SO ₄ , filtered and then evaporated to dryness.

The residue obtained is purified by flash chromatography on silica gel (ethyl acetate / cyclohexane 2: 8, v / v) to give 0.830 g (63%) of the expected product 3,4,5-trimethoxybenzoate (S) 2 - (Chloromethoxycarbonyl methylamino) -2-phenyl-n-butyl as a colorless oil.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.92 (t, J = 7.2Hz, 3H, CH _3); 2.24 (m, 1H, CH ₂ diastereotope); 2.45 (m, 1H, CH ₂ diastereotope); 3.03 (s (1), 3H, NCH ₃ ); 3.89 (s, 6H, 2xOCH ₃ ); 3.91 (s, 3H, OCH ₃ ); 4.99 (s (1), 2H, OCH ₂ ); 5.71 (s (1), 2H, ClCH ₂ ); 7.17-7.37 (m, 7H, ArH). MS (Cl, NH ₃ ): m / z (%) = 483 [(M + NH ₄ ) ⁺ , 65], 465 [(M ⁺ "), 10], 343 [(MH-C ₃ O ₂ NCIH ₅ ) ^+, 100] R _f (SiO _2, ^ethyl acetate / cyclohexane, 3: 7.): 0.41

2nd step

0.289 g (0.62 mmol, 1 eq) of (S) 2- (chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate are dissolved in 10.2 ml of N N, N-dimethylformamide then placed at 0 ° C. A whitish suspension of 0.125 g (0.62 mmol, 1 eq) of cesium acetate in 4.1 ml of N, N-dimethylformamide is then added slowly. Stirring is maintained ^for 17 hours at room temperature. An additional 0.038 g (0.18 mmol, 0.3 eq) of cesium acetate is then added and stirring is continued for 7 hours at room temperature.

The reaction mixture is then diluted in 20 ml of ethyl acetate. The organic phase is washed with 2x12 ml of NaHCO ₃ (10%), 2 × 12 ml of water and 12 ml of saturated NaCl, dried over Na ₂ SO ₄ , filtered and evaporated to dryness.

The residue obtained is purified by flash chromatography on silica gel (gradient ethyl acetate / cyclohexane 1: 9 to 3: 7, v / v) to give 0.065 g (20%) of the expected product 3,4,5-trimethoxybenzoate (S) 2- (acetoxymethoxycarbonylmethylamino) -2-phenyl-n-butyl as a colorless oil.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.80 (t, J = 6.5Hz, 3H, CH _3); 1.92 (s, 3H, CH ₃ CO); 2.13 (s (1), 1H, CH ₂ diastereotope); 2.35 (m, 1H, CH ₂ diastereotope); 2.93 (s (1), 3H, NCH ₃ ); 3.80 (s, 6H, 2xOCH ₃ ); 3.82 (s, 3H, OCH ₃ ); 4.82 (d, J = 1 0.6 Hz, 1H, CH ₂ diastereotope); 4.96 (m, 1H, OCH ₂ diastereotope); 5.57 (s (1), 2H, OCH ₂ O); 7.10-7.27 (m, 7H, ArH). MS (Cl, NH ₃ ): m / z (%) = 479 [(M + NH ₄ -C ₂ H ₅ ) ⁺ , 100], 285 [15], 230 [15].

R _f (SiO ₂ , ethyl acetate / cyclohexane 3: 7): 0.21.

Example 3 Synthesis of ORC007

0.40 g (1.07 mmol, lq) of (S) -2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate is placed under nitrogen and then dissolved in 53 ml of dichloromethane. 1.3 ml (2.53 mmol, 2.36 eq) of a 20% solution in toluene of phosgene and then 0.16 ml (1.18 mmol, l, Iq) of triethylamine are then added. Stirring is maintained for 22 hours at room temperature. 0.69 g (5.35 mmol, 5 eq) of 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-one are then added. After an additional 24 hours at room temperature, the reaction mixture is washed with 2 × 40 ml of water and 1 × 40 ml 1M HCl. The organic phase is dried over Na ₂ SO ₄ , filtered and then evaporated to dryness.

The residue obtained is purified by 2 flash chromatographies on silica gel (dichloromethane and then gradient ethyl acetate / cyclohexane 1: 9 to 3: 7, v / v) to give 0.085 g (15%) of the expected product 3,4, (S) 2- (5-methyl-1,3-dioxol-2-one-4-ylmethylamino) -2-phenyl-n -butyl 5-trimethoxybenzoate as a colorless oil.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.78 (t, J = 7.2 Hz, 3H, CH ₃ ); 1.94 (s, 3H, CH ₃ ); 2.02 (m, 1H, CH ₂ diastereotope); 2.32 (m, 1H, CH ₂ diastereotope); 3.02 (s (1), 3H, NCH ₃ ); 3.80 (s, 6H, 2xOCH ₃ ); 3.82 (s, 3H, OCH ₃ ); 4.64 (s (1), 2H, OCH ₂ Csp ₂ ); 4.80 (m, 1H, OCH ₂ diastereotope); 4.93 (m, 1H, OCH ₂ diastereotope); 7.10-7.27 (m, 7H, ArH).

MS (Cl, NH ₃ ): m / z (%) = 547 [(M + NH ₄ ) ⁺ , 5], 479 [80], 260 [100]. R _f (SiO ₂ , dichloromethane / methanol, 98: 2): 0.16. Example 4 Synthesis of ORC020

ORC002 ORC020

Step 1: In a 100 ml three-necked flask, under a stream of nitrogen, (S) -2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (1.49 g, 4.0 mmol; eq.) is dissolved in 40 ml of dichloromethane. The solution is cooled to 0 ° C. A solution of phosgene in toluene at 20% (4.95 ml, 9.4 mmol, 2.4 eq) and then N, N-diisopropylethylamine (730 μl, 4.4 mmol, 1.1 eq) are added. without exceeding 5 ° C. The ice bath is removed and the mixture is stirred for 20 hours. There is obtained (S) 2- (chloroformylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate.

2nd step :

2.53 ml of 4-methoxybenzyl alcohol (20 mmol, 10 eq.) Are dissolved in 10 ml of dichloromethane and then half of the volume of the reaction mixture (871.8 mg, 2 mmol, 1 eq.) Of 3 (S) 2- (chloroformylmethylamino) -2-phenyl-n-butyl 4,5-trimethoxybenzoate (step 1), ie 20 ml of the solution obtained, are added dropwise. After 1 hour at room temperature, N, N-diisopropylethylamine (1.30 ml, 8 mmol, 4 eq) is added and stirring is continued for 20 hours. The reaction mixture is poured into 20 ml of saturated NH ₄ Cl solution (pH = 7-8). After decantation, the aqueous phase is extracted with 2x20 ml of dichloromethane. The organic phases are combined and washed with 2 × 20 ml of a saturated solution of NH ₄ Cl (pH = 7 then pH = 6), and 20 ml of a solution of half-saturated NaCl and then dried with Na ₂ SO ₄ . The crude product is purified on silica gel (35 parts, eluent ethyl acetate / cyclohexane 7/3 to obtain a transparent oil of 3,4,5-trimethoxybenzoate of (S) 2- (4-methoxybenzyloxycarbonyl methyl amino) -2-phenyl-n-butyl (15%, 170 mg) The oil is taken up in 1 ml of ether and 1 ml of pentane to obtain an emulsion that remains. The flask is cooled for 2 hours at 4 ° C and then the solvent supernatant is removed by a pasteur pipette. The solid is dried at the vane pump to give a white foam.

R _f (SiO ₂ , ethyl acetate / cyclohexane 7: 3): 0.42 1H-NMR (CDCl ₃ , 400MHz): δ (ppm) = 0.86 (t, J = 7.3 Hz, 3H) ; 2.16 (qd, J = 7.3 Hz and 14.8 Hz, 1H, CH ₂ ); 2.38 (qd, J - 7.3 Hz and 14.8 Hz, 1H, CH ₂ ); 3.09 (si, 3H); 3.80 (s, 3H); 3.87 (s, 6H); 3.91 (s, 3H); 4.93 (ml, 4H); 6.79 (m, 2H); 7.05 (ml, 1H); 7.18 (m, 2H); 7.30 (m, 6H).

MS (Cl, NH ₃ ): m / z = 555 [(M + NH ₄ ) ⁺ ], 537, 494, 463, 268. Example 5

Synthesis of ORC009:

ORC009

0.081 g (0.54 mmol, 1 eq) of 4-acetamidophenol under nitrogen was suspended in 3.6 ml of dry ethyl acetate and placed at 0 ° C. 0.43 ml (0.82 mmol, 1.54 eq) of a 20% solution in toluene of phosgene are then added. 0.075 ml (0.54 mmol, 1 eq) of triethylamine are then added (still at 0 ° C.). It is then placed at room temperature. After 1 hour, 0.40 g (1.07 mmol, 2 eq) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate are added. Stirring is continued for 18 hours at room temperature. The reaction mixture is diluted in 5 ml of ethyl acetate and then washed with 8 ml of water and 8 ml of 1M HCl. The organic phase is dried over Na ₂ SO ₄ , filtered and then evaporated to dryness.

The residue obtained is purified by flash chromatography on silica gel (gradient dichloromethane to dichloromethane / methanol 9: 1, v / v). The product obtained is triturated twice in 1.5 ml of pentane / ether 1: 1 to give 0.092 g (31%) of a white solid 3,4,5-trimethoxybenzoate of (S) 2- (4-acetylaminophenyloxycarbonyl methylamino -2-phenyl-n-butyl.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.86 (t, J = 6.8Hz, 3H, CH _3); 2.02 (s, 3H, CH ₃ CO); 2.18 (m, 1H, CH ₂ diastereotope); 2.43 (m, 1H, CH ₂ diastereotope); 3.06 (s (1), 3H, NCH ₃ ); 3.79 (s, 6H, 2xOCH ₃ ); 3.83 (s, 3H, OCH ₃ ); 4.87 (d, J = I l ₅ IHZ, IH, diastereotopic CH _2); 5.03 (m, 1H, CH ₂ diastereotope); 6.70 (s (1), 1H, NH); 7.14-7.37 (m, 1H, ArH).

MS (Cl, NH ₃ ): m / z (%) = 568 [(M + NH 4) ⁺ , 90], 374 [(MH-C ₉ O ₃ NH 4) ⁺ , 10], 343 [(MH-C ₁₀ O ₃ N ₂ Hn) ⁺ , 40].

Rf (SiO ₂ , dichloromethane / methanol 98: 2): 0.28

Example 6 Synthesis of ORC021

ORC002 ORC021

To the solution of 300 mg (0.8 mmol, 1 eq) of (S) -methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate in 3 ml of dichloromethane, 400 μl (2 ml) 4 mmol, 3 eq) of DIPEA are added dropwise at room temperature under nitrogen and then 337 μl (2.4 mmol, 3 eq) of 4-chlorophenyl chloroformate dropwise. The mixture is stirred at room temperature for 70 hours. The reaction mixture is poured into 30 ml saturated NaHCO ₃ (pH = 7), then extracted with 30 ml of dichloromethane and then 10 ml of dichloromethane. The organic phase is washed with 20 ml saturated NaCl (pH = 7-8) and then dried over Na ₂ SO ₄ and evaporated to dryness to give an oil. This is purified on a column of silica gel (50 parts, eluent ethyl acetate / cyclohexane 2/8). The oil obtained is cooled to -50 ° C under nitrogen to precipitate the product, 2x2 ml of pentane are added. The product is then dried under vacuum for 1 hour to give a white powder containing 4% of solvent which can not be evaporated. The powder is solubilized in 1 ml of CH ₂ Cl ₂ and then evaporated to dryness to give the pump a white foam of (S) 2- (4-chlorophenoxycarbonylmethylamino) 3,4,5-trimethoxybenzoate after 20 hours. phenyl-n-butyl (360 mg, 85%).

R _f (SiO ₂ , ethyl acetate / cyclohexane 4: 6): 0.66 1H-NMR (CDCl ₃ , 400MHz): δ (ppm) = 0.94 (t, J = 7.4 Hz, 3H) ; 2.27 (m, 1H, CH ₂ ); 2.51 (qd, J = 7.4 Hz and 14.6 Hz, 1H, CH ₂ ); 3.20 (si, 3H); 3.88 (s, 6H); 3.92 (s, 3H); 5.00 (dd, J = 10.4 Hz and J = 61.1 Hz, 2H, CH ₂ ); 6.80 (si, 2H); 7.23 (ml, 3H); 7.29 (m, 2H); 7.38 (m, 4H).

MS (Cl, NH ₃ ): m / z = 545 [(M + NH ₄ ) ⁺ ], 343, 195. Example 7 Synthesis of ORCOl 8:

CH ₃ CH ₂ SCOCI

ORC002 ORC018

To a solution of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (300 mg, 0.8 mmol, 1 eq) in dichloroethane is added at room temperature under nitrogen, dropwise, N, N-diisopropylethylamine (0.4 ml, 2.4 mmol, 3 eq.), and then dropwise, ethyl chlorothioformate (260 μl, 2.4 mmol, 3 eq. .). Stirring is maintained at room temperature for 70 hours. The reaction mixture is poured into 30 ml of saturated NaHCO ₃ (pH = 7), then extracted with 30 ml of dichloromethane, and 10 ml of dichloromethane. The organic phase is washed with 20 ml saturated NaCl (pH = 7-8) and then dried over Na ₂ SO ₄ and evaporated to dryness. The oil obtained is dissolved in 3 ml of ether, then under gentle heating, 3 ml of pentane are added dropwise. The cloudy solution is placed cold for 20 hours and then the supernatant is removed with a pipette. The operation is carried out twice with 5 ml of ether / pentane. The crystals are then dried in the flask to obtain a white (S) 2- (ethylthiocarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate powder (251 mg, 68%).

R _f (SiO ₂ , ethyl acetate / cyclohexane 1: 3): 0.50.

¹ H-NMR (CDCl _3, 400MHz): δ (ppm) = 0.93 (t, J = 7.4 Hz, 3H); 1.24 (t, J = 7.3 Hz, 3H); 2.22 (qd, J = 7.4 Hz and 14.3 Hz, 1H, CH ₂ ); 2.41 (qd, J = 7.4 Hz and 14.3 Hz, 1H, CH ₂ ); 2.83 (q, J = 7.3 Hz, 2H); 3.02 (s, 3H); 3.88 (s, 6H); 3.90 (s, 3H); 4.99 (d, J = 11.3 Hz, 1H, CH ₂ ); 5.11 (d, J = 1.3 Hz, 1H, CH ₂ ); 7.16 (si, 2H); 7.26 (m, 1H); 7.34 (m, 4H).

MS (Cl, NH ₃ ): m / z = 479 [(M + NH ₄ ) ⁺ ], 462 [(M + H) ⁺ ], 343, 250. Example 8 ORC033

ORC033

Under a nitrogen atmosphere, nicotinic acid (0.081 g, 0.00064 mol) is solubilized in DMF (1 mL). Cesium fluoride (0.098 g, 0.00064 mol) is added and the solution is stirred at room temperature for 15 minutes. The solution is cooled to 0 ° C. and (S) 2- (chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (100.0 mg, 0.0002146 mol), previously solubilized. in DMF (1 mL) is added dropwise. The mixture is heated at 70 ° C for 17 hours.

After cooling, ethyl acetate (5 mL) is added and the organic phase is washed with saturated NaHCO 3 solution and then with saturated sodium chloride solution. The organic phase is dried over Na 2 SO 4, filtered and evaporated to give 120 mg of yellow oil. The product is purified [(SiO2, cyclohexane / AcOEt (3/7)] to give 86 mg of (S) -2- (nicotinyloxymethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate. form of a white amorphous solid.

. TLC: SiO2, cyclohexane / AcOEt (3/7) Rf 0.37

. 1H NMR (CDCl3): δ 0.86 (3H, t, J = 7.55Hz, CH3-CH2), 2.10-2.22 (1H, m, CH-CH3), 2.40-2, 48 (1H, m, CH-CH 3), 3.09 (3H, br s, NCH 3), 3.85-3.88 (9H, d, J = 9.79 Hz, 3 OCH 3), 4.95 (2H, br d, J = 9.61Hz, CH 2 -O), 5.91 (2H, br s, CH 2), 7.14 (2H, s, H arom), 7.25-7, 39 (8H, m, H arom), 8.20 (1H, br s, Hpyr), 8.77-8.80 (1H, dd, J1 = 1.69 Hz, J2 = 4.89 Hz, Hpyr), 9.15 (1H, brs, Hpyr).

. MS (ES +): [M + H] +, m / z: 552 Example 9 ORC035

Under a nitrogen atmosphere, N-carbobenzyloxyglycine (0.20 g, 0.00096 mol) is solubilized in DMF (2 mL). Sodium fluoride (0.15 g, 0.00096 mol) is added and the mixture is stirred for 15 minutes at room temperature.

The mixture is cooled to 0 ° C. and (S) 2- (chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (150.0 mg, 0.0003219 mol) in solution in DMF (2 mL) is added dropwise. The reaction mixture is heated at 70 ^° C. for 2 hours. After cooling, ethyl acetate (8 mL) is added and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate (3 mL), then a solution of saturated sodium chloride (3 mL), then the organic phase is dried over Na 2 SO 4, filtered and then evaporated to give a yellow oil. The product is purified: SiO2, cyclohexane / AcOEt (7/3 and then 6/4) to give 197 mg of (S) -2- (benzyloxycarbonylaminoacetoxymethoxycarbonylmethylamino) -2,4-thiophenyl-n-butyl 3,4,5-trimethoxybenzoate in the form of yellow oil.

TLC: SiO2, cyclohexane / AcOEt (3/7) Rf 0.50

¹ H NMR (CDCl ₃ ): δ (ppm) = 0.85 (3H, t, J = 7.53 Hz, CH ₃ -CH ₂ ), 2.08-2.27 (1H, m, CH ₂ CH ₂ ) ₃ ), 2.36-2.46 (1H, m, CH-CH ₃ ), 3.05 (3H, brs, NCH ₃ ), 3.85-3.90 (9H, d, J = 8, 29 Hz, 3 OCH ₃ ), 4.86 (2H, br s, CH ₂ -O), 5.11-5.20 (4H, m, 2 CH 2), 5.70 (2H, br s, CH ₂ ), 7.16 (2H, s, H _arom ), 7.25-7.40 (1OH, m, H ₃₁ - _O1n )

MS (ES +): [M + Na] +, m / z: 638 Example 10 ORC036

Under a nitrogen atmosphere, N-acetyl-glycine (0.075 g, 0.00064 mol) is solubilized in DMF (1 mL, 0.01 mol). Cesium fluoride (0.098 g, 0.00064 mol) is added and the mixture is stirred for 15 minutes at room temperature. The mixture is cooled to 0 ° C. and (S) 2- (chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate (100.0 mg, 0.0002146 mol) dissolved in DMF (1 mL) is added dropwise. The reaction mixture is heated at 70 ^° C. for 17 hours.

After cooling, ethyl acetate (5 mL) is added and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate, then an aqueous solution of saturated sodium chloride (2 mL), finally dried. on Na2SO4, filtered and evaporated to give (S) -2- (acetylaminoacetoxymethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate as a yellow oil (205 mg).

TLC: SiO2, cyclohexane / AcOEt (1/9) Rf 0.34

1H NMR (CDCl3): δ (ppm) = 0.86 (3H, t, J = 7.34 Hz, CH3-CH2), 2.04 (3H, s, CH3-CO), 2.18-2, 26 (1H, m, CH-CH3), 2.32-2.57 (1H, m, CH-CH3), 3.05 (3H, brs, NCH3), 3.86-3.90 (9H, m.p. d, J = 6.97 Hz, 3 OCH 3), 3.96 (2H, br s, CH 2), 4.83-4.90 (1H, br d, J = 0.54 Hz, CH 2 O). , 5.03-5.06 (1H, br s, CH 2 O), 5.66-5.74 (2H, br s, CH 2), 5.91-5.95 (1H, br s), 7. , 17 (2H, s, H arom), 7.24-7.37 (5H, m, H arom).

MS (ES +): [M + Na] +, m / z: 546 Example 11 ORC037

ORC037

Step 1

Under nitrogen atmosphere, (S) -2-amino-2-phenyl-butan-1-ol (15.0 g, 0.0908 mol) is solubilized in methylene chloride (150 mL). 1-hydroxybenzotriazole (13.5 g, 0.0998 mol), methoxyacetic acid (7.82 mL, 0.0998 mol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide, hydrochloride (19 5 g, 0.0998 mol) are added. The resulting colorless solution is stirred at room temperature for 4 days.

The mixture is washed with 0.1N HCl (100 mL) and then a saturated solution of sodium chloride (100 mL). The organic phase is dried over Na 2 SO 4, filtered and concentrated to give 22.4 g of orange oil, which is chromatographed: SiO 2, CH 2 Cl 2 / MeOH (99/1 and 98/2) to give 13.12 g of slightly yellow solid. .

¹ H NMR (CDCl ₃ ): δ 0.83 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.97-2.18 (2H, m, CH ₂ -CH ₃ ), 3.49 (3H, s, OCH ₃ ), 3.82-4.10 (4H, m, 2 CH ₂ ), 5.03 (1H, t, J = 6.78Hz, OH), 7.09; (1H, br s, NH), 7.28-7.42 (5H, m, H _arom ).

2nd step

13.120 g, 0.055290 mol of (N - ((S) -1-hydroxymethyl-1-phenylpropyl) -2-methoxyacetamide) are solubilized in THF (100 ml) under a nitrogen atmosphere. The cooled solution at 10 ° C., then borane-dimethyl sulfide complex (16 mL, 0.16 mol) is added dropwise. The mixture is stirred at room temperature for 2 days. 70 ml of methanol are added slowly and the solution is stirred for 15 minutes. 100 ml of a 10% potassium carbonate solution and then 40 ml of ethyl acetate are added. The organic phase is washed with saturated sodium chloride solution (100 mL), dried over Na 2 SO 4, filtered and then evaporated to give 12.4 g of yellow oil. ¹ H NMR (CDCl ₃ ): δ (ppm) = 0.69 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.73-1.82 (1H, m), 1, 90- 2.01 (1H, m), 2.53-2.67 (2H, m, CH ₂ ), 3.30 (3H, s, OCH ₃ ), 3.48 (2H, m, CH 2), 3.86 to 3.98 (2H, dd, J _/ = 10.90 Hz, J ₂ = I 5.07 Hz), 7.24 to 7.40 (5H, m, _arom H).

Step 3 12.40 g (0.05553 mol) of ((S) -2- (2-methoxy-ethylamino) -2-phenyl-butan-1-ol) is introduced into a flask fitted with a distillation elbow, then solubilized in a toluene mixture (400 mL) / ethanol (20 mL).

18.71 g (0.08107 mol) of the methyl ester of 3,4,5-trimethoxy-benzoic acid are added. The solution is then heated to 130 ° C.

1.5 g, 0.028 mol of sodium methoxide is added portionwise at 130 ^° C. The white suspension obtained is stirred at 130 ° C. for 17 hours. Again 1.0 g of sodium methoxide is added portionwise at 130 ° C and the suspension is stirred for a further 3 hours. After cooling, the reaction mixture is evaporated and then taken up with a solution of 3N NaOH (200 mL).

The mixture is stirred for 15 minutes and then extracted with ethyl acetate (300 mL).

The organic phase is washed with saturated sodium chloride solution (200 ml), dried over Na 2 SO 4, filtered and evaporated to give 18.6 g of (S) -2- (2-methoxyethylamino) 3,4,5-trimethoxybenzoate -2-phenyl-n-butyl in the form of an orange oil.

The product is purified: SiO2, CH2Cl2 then CH2Cl2 / MeOH (95/5) to give 8.3 g of yellow oil

TLC: SiO2, CH2Cl2 / MeOH (95/5) Rf 0.41

1H NMR (CDCl3): δ (ppm) = 0.80 (3H, t, J = 7.34 Hz, CH3-CH2), 1.82-1.93 (2H, m), 2.51-2, 57 (1H, m), 2.64-2.72 (1H, m), 3.31 (3H, s, OCH3), 3.46-3.51 (2H, m, CH2), 3.85- 3.90 (9H, d, J = 8.47 Hz, 3 OCH3), 4.51-4.67 (2H, dd, J1 = 1.11Hz, J2 = 24.30Hz), 7.21. -7.53 (7H, m, H arom).

MS (ES +): [M + H] +, m / z: 417

(S) 2-Amino-2-phenyl-n-butanol may be prepared according to the method described in applications FR 2 765 218 and EP 510 168.

Example 12 ORC050

ORC050

Step 1

3,4,5-Trimethoxy-benzoic acid (S) -2-methylamino-2-phenyl-butyl ester (2.0 g, 0.0054 mol), under a nitrogen atmosphere, is solubilized. in methylene chloride (20 mL). 1-hydroxybenzotriazole (796 mg, 0.00589 mol), methoxyacetic acid (541 mg, 0.00589 mol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (1150 mg, 0.00589) mol) are added. The colorless solution is stirred at 40 ^° C. for 2 days. The mixture is washed with 0.1 N hydrochloric acid (20 mL) and then with saturated sodium chloride solution (20 mL). The organic phase is dried over Na 2 SO 4, filtered and evaporated to give 1.84 g of yellow oil. The product is purified: SiO 2, cyclohexane / AcOEt (1/1) to give 796 mg of yellow oil.

TLC: SiO2, cyclohexane / AcOEt (1/1) Rf 0.65

1H NMR (CDCl 3): δ (ppm) = 0.91 (3H, t, J = 7.34 Hz, CH 3 -CH 2), 2.18-2.26 (1H, m), 2.38-2, 46 (1H, m), 2.94 (3H, s, NCH 3), 3.41 (3H, s, OCH 3), 3.85-3.90 (9H, d, J = 9.79 Hz, 3 OCH 3 ), 4.09 (2H, br s, CH 2), 4.99 (1H, d, J = 1.49 Hz), 5.25 (1H, d, J = 1, 1.49Hz), 7, 11 (2H, s, H arom), 7.21-7.39 (5H, m, H arom).

2nd step

335 mg of the above product are solubilized in THF (1 mL). 0.28 mL (0.0030 mol) of borane-dimethyl sulphide complex is added dropwise and the mixture is stirred at room temperature for 3 days. Methanol (0.7 mL) is added to the reaction mixture and the solution is stirred for 30 minutes. A solution of 10% potassium carbonate (1 mL) and then 3 mL of ethyl acetate (3 mL) are added. The organic phase is washed with a saturated solution of sodium chloride (1 mL), dried over Na 2 SO 4, filtered and evaporated to give 135 mg of slightly yellow oil. The product is purified: SiO 2, cyclohexane / AcOEt (7/3) to give 221 mg of (S) -2- (2-methoxyethylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate under form of a colorless oil.

¹ H NMR (CDCl ₃ ): δ (ppm) = 0.68 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.87 (2H, q, J = 7.35 Hz, CH ₂ -CH ₃ ), 2.44 (3H, s, NCH ₃ ), 2.84 (2H, t, J = 6.59 Hz, CH ₂ ), 3.28 (3H, s, OCH ₃ ), 3.44 (2H, t, J = 6.59 Hz), 3.82-3.90 (9H, d, J = I 6.58 Hz, 3 OCH ₃ ), 4.75-4.84 (2H). , dd, Hz, J ₂ = I 1.87 Hz, CH ₂ ), 7.21-7.50 (7H, m, H ₃ T _01n ).

MS (ES +): [M + H] +, m / z: 431 Example 13 ORC051

ORC051 Under nitrogen, 200.0 mg (0.0005356 mol) of (R) 2- (chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate are solubilized in methylene chloride. (1.0 mL). The colorless solution is cooled to -1 ° C and chloromethyl chloroformate (210 mg, 0.0016 mol) is added dropwise. The reaction mixture is stirred at room temperature for 17 hours. The colorless solution is then cooled to -5 ° C and chloromethyl chloroformate (0.106 mg, 1.5 eq) is added dropwise again. The solution is stirred at ambient temperature for 3 hours. The mixture was cooled to 0 ° C and chloromethyl chloroformate (106 mg, 1.5 eq) was added dropwise again. The solution is stirred at room temperature for 2 hours, then heated at 40 ° C for 1 hour, and then stirred at room temperature for 15 hours.

The organic phase is treated with a saturated solution of bicarbonate (3.0 mL), after adding 3 mL of methylene chloride. The organic phase is washed with a saturated solution of sodium chloride (3.0 mL), dried over Na 2 SO 4, filtered and then evaporated to give 150 mg of a slightly yellow oil. ¹ H NMR (CDCl ₃ ): δ (ppm) = 0.90 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 2.17-2.24 (1H, m, CH ₂ CH ₂ ) ₃ ), 2.36-2.46 (1H, m, CH-CH ₃ ), 3.01 (3H, brs, NCH ₃ ), 3.87-3.89 (9H, d, J = 5, 84 Hz, 3 OCH ₃ ), 4.93-4.97 (2H, br d, J = I 0.55 Hz, CH ₂ -O), 5.69 (2H, br s, CH ₂ -Cl), 7.17 (2H, s, Ar H _o m), 7.25-7.36 (5H, m, _arom H).

Step 2: Under nitrogen atmosphere, 3,4,5-trimethoxy-benzoic acid (R) -2- (chloromethoxycarbonylmethylamino) -2-phenyl-butyl ester (150.0 mg. , 0003219 mol) is solubilized in DMF (2.0 mL). The solution is cooled to 0 ° C and sodium acetate (195 mg, 0.000965 mol) solubilized in DMF (2.0 mL) is added dropwise. The mixture is heated at 70 ° C for 15 hours. After cooling, ethyl acetate (13.0 mL) and saturated bicarbonate solution (13.0 mL) are added.

The mixture is stirred for 15 minutes at room temperature. The organic phase is washed with is washed with a saturated solution of sodium chloride (10 mL), dried over NaSO4, filtered and then evaporated to give a yellow oil. The product obtained is purified on a column: SiO 2, Cyclohexane / AcOEt (8/2) to give, after evaporation, 1 16 mg of (R) -2- (3,4-trimethoxybenzoate) -2- (acetoxymethoxycarbonylmethylamino) -2- phenyl-n-butyl in the form of a yellow oil.

TLC: SiO2, Cyclohexane / AcOEt (1/1) Rf: 0.64

1H NMR (CDCl3): δ (ppm) = 0.87 (3H, t, J = 7.34 Hz, CH3-CH2), 1.99 (3H, br s, CH3-CO), 2.14-2. , 23 (1H, m, CH-CH3), 2.40-2.47 (1H, m, CH-CH3), 3.01 (3H, brs, NCH3), 3.87-3.89 (9H, d, J = 5.65 Hz, 3 OCH 3), 4.87-4.92 (2H, br d, J-10.73 Hz, CH 2 -O), 5.65 (2H, brs, CH 2 -Cl), 7.17 (2H, s, H arom), 7.25-7.36 (5H, m, H arom).

MS (ES +): [M + NH] +, m / z: 507 EXAMPLE 14 ORC 052

ORC052

Step 1 :

In an autoclave, sodium hydroxide (17.120 g, 0.42803 mol) is solubilized in water (74 mL, 4.1 mol), followed by (5R) -5-ethyl-5-phenylimidazolidine-2 , 4-dione (20.0 g, 0.0979 mol) is added portionwise. The reaction mixture is heated at 130 ^° C. with stirring for 48 hours. The mixture is cooled and a white precipitate is formed.

The pH is brought to 7 and the precipitate is washed with ethyl acetate. The mixture is diluted in 30OmL of water cooled to 0 ° C. The pH is brought to 1 with 12 M HCl (50.0 mL). The precipitate is completely solublilized. While maintaining the mixture at 0 ° C, the pH is reduced to 7 with 20 mL of a 5N NaOH solution to obtain a white precipitate. The mixture is filtered, the precipitate is washed with water (150 mL) and then dried under vacuum at 40 ⁰ C to give 22.8 g of a white solid.

¹ H NMR (MeOD): δ (ppm) = 1.06 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 2.30-2.38 (2H, m, CH ₂ -CH) ₃ ), 7.33-7.46 (3H, m, H _arom ), 7.55-7.59 (2H, m, H, J.

Step 2: Under a nitrogen atmosphere, (2R) -2-amino-2-phenylbutanoic acid (21.60 g, 0.1205 mol) is solubilized in THF (200 mL). Borane-THF IM dissolved in THF (94 mL, 0.96 mol) is added dropwise.

The mixture is heated at 70 ^° C. with stirring for 48 hours. Borane-THF IM dissolved in THF (47 mL, 4 eq) is added dropwise. The mixture is heated at 70 ° C for 2 hours. The operation is renewed.

The mixture is finally cooled to 0 ^° C. and then a saturated solution of sodium bicarbonate (100.0 ml) is added. After addition of methylene chloride, the organic phase is washed with a saturated solution of sodium chloride, finally dried over Na 2 SO 4, then filtered and evaporated to give 13.06 g of a slightly yellow solid. ¹ H NMR (MeOD): δ (ppm) = 0.59 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.57-1.69 (1H, m, CH-CH ₃ ), 1.71-1.84 (1H, m, CH-CH ₃ ), 3.52-3.61 (2H, dd, J _/ = 10.92 Hz, J ₂ = 4.14 Hz, CH ₂ -OH), 7.09 to 7.33 (5H ₅ _5H Hi _3101n).

Step 3: Under nitrogen atmosphere, (R) -2-amino-2-phenyl-butano-lol (13.060 g, 0.079040 mol) is solubilized in methylene chloride (300 mL). Methoxyacetic acid (7.99 g, 0.0869 mol), 1-hydroxybenzotriazole (1 1.8 g, 0.0870 mol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiirnide, ( HCl) (16.70 g, 0.08537 mol) are added directly to the mixture with a minimum of methylene chloride. The solution is stirred at ambient temperature for 17 hours. The mixture was washed with 0.1M HCl (300.0 mL). The aqueous phase is extracted with methylene chloride (3 times 200.0 mL).

The organic phases are combined, washed with saturated sodium chloride solution (600.0 ml), dried over Na 2 SO 4, filtered and then evaporated to give 14 g of a yellow oil. The product is purified: SiO 2, CH 2 Cl 2 / MeOH (99/1, 98/2, 100% MeOH) to give 5.17 g of a slightly yellow oil.

¹ H NMR (CDCl ₃ ): δ (ppm) = 0.83 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.96-2.16 (2H, m, CH ₂ - CH ₃ ), 3.49 (3H, s, OCH ₃ ), 3.82-4.10 (4H, m, 2 CH ₂ ), 5.03 (1H, t, J = 6.78 Hz, OH) , 7.09 (1H, br s, NH), 7.26-7.42 (5H, m, H n-).

Step 4: Under nitrogen atmosphere, N- (1-hydroxymethyl-1-phenylpropyl) -2-methoxyacetamide (5.170 g, 0.02179 mol) is solubilized in THF (50.0 mL,) . The mixture is cooled to 10 ° C. and then borane-dimethyl sulphide complex (6.2 ml, 0.065 mol) is added dropwise. The mixture is stirred at room temperature for 24 hours. The mixture is cooled to 10 ° C. and then borane-dimethyl sulfide complex (6.2 mL, 3 eq) is added dropwise. The mixture is stirred at room temperature for 3 hours. The mixture is then cooled to 0 ^° C. and methanol (27.0 ml) is added dropwise. 4OmL of a 10% solution of potassium carbonate, then 8OmL of ethyl acetate are added to the mixture. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over Na 2 SO 4, filtered and then evaporated to give 4.92 g of a yellow oil.

¹ H NMR (CDCl ₃ ): δ (ppm) = 0.66 (3H, t, J = 7.34 Hz, CH ₃ -CH ₂ ), 1.53-1.69 (1H, m), 1, 73-1.69 (1H, m), 2.40-2.60 (2H, m, CH ₂ ), 3.36 (3H, s, OCH ₃ ), 3.43-3.48 (2H, m). , CH ₂ ), 3.72- 3.88 (2H, dd, J _/ = 10.90 Hz, J ₂ = 5.07 Hz), 7.21-7.40 (5H, m, H _arom ) .

Step 5: In a flask equipped with a distillation elbow, (R) -2- (2-methoxy-ethylamino) -2-phenylbutan-1-ol (4.840 g, 0.02167 mol) is solubilized in a toluene mixture. (150 mL) / methanol (7.60 mL). The 3,4,5-trimethoxy-benzoic acid methyl ester (5.50 g, 0.0238 mol) is added and the mixture is heated to 130 ° C. Sodium methoxide (0.58 g, 0.011 mol) is added portionwise and the mixture is stirred at 130 ° C for 3 hours.

Sodium methoxide (0.47 g, 0.0087 mol) is again added portionwise and the mixture is stirred at 130 ° C for 15 hours. The mixture is cooled and then evaporated. 7OmL of a 3M aqueous solution of sodium hydroxide are added and the mixture is stirred for 15 minutes before being extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over Na 2 SO 4, filtered and then evaporated to give 8.87 g of an orange oil. The product is purified on a column: SiO 2, Cyclohexane / AcOEt (9/1, 8/2) and then 100% AcOEt) to give 4.37 g of 3,4,5-trimethoxybenzoate of (R) -2- (2- methoxyethylamino) -2-phenyl-n-butyl as a slightly yellow oil. TLC: SiO2 CH2Cl2 / MeOH (95/5); Rf: 0.34

1H NMR (CDCl3), δ (ppm) = 0.80 (3H, t, J = 7.34Hz, CH3-CH2), 1.79-1.95 (2H, m), 2.50-2, 57 (1H, m), 2.64-2.72 (1H, m), 3.31 (3H, s, OCH3), 3.46-3.51 (2H, m, CH2), 3.86- 3.89 (9H, d, J = 8.28 Hz, 3 OCH3), 4.51-4.67 (2H, dd, J1 = 1.11Hz, J2 = 24.30Hz), 7.21. -7.53 (7H, m, H arom). MS (ES +): [M + H] +, m / z: 417. Example 15 ORC055

Under nitrogen, 500 mg (1.34 mmol, 1.0 eq) of (S) -2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate are dissolved in 1 ml of dichloromethane. The mixture is cooled to 20 ^° C. At this temperature, 440 μl (4.0 mmol, 3.0 eq) of α-chloroethyl chloroformate are added dropwise. The mixture is stirred at ambient temperature for 5 hours. The reaction is monitored by TLC. The dichloromethane is evaporated with nitrogen.

The residue obtained as a colorless oil used in ^the next step without further purification. ¹ H-NMR (CDCl _3, 300MHz): δ (ppm) = 0.94 (m, 3H, CH _3); 1.59 (m, 3H, CH ₃ ); 2.22 (m, 1H, CH ₂ diastereotope); 2.45 (m, 1H, CH ₂ diastereotope); 3.08 (br, 3H, NCH ₃ ); 3.90 (s, 3H, OCH ₃ ); 3.91 (s, 3H, OCH ₃ ); 3.92 (s, 3H, OCH ₃ ); 5.00 (br, 2H, OCH ₂ ); 6.48 (br, 1H, ClCH); 7.19-7.39 (m, 7H, ArH). R _f (SiO ₂ , cyclohexane / ethyl acetate, 6/4): 0.8 Step 2:

The (S) 2 - [(1-chloro-ethoxycarbonyl) methyl-amino] -2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate obtained in the previous step is dissolved in 2 ml of N N, N-dimethylformamide. 807 mg (3.67 mmol, 2.7 eq) of cesium isobutyrate are added. The mixture is stirred at 55 ° C overnight. The reaction is monitored by TLC.

10 ml of water are added to the mixture. The product is extracted with ethyl acetate (3 × 10 mL) and then the organic phase is washed successively with water and saturated sodium chloride solution (15 mL). The organic phases are dried over Na ₂ SO ₄ , filtered and then concentrated to dryness to restore a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate: 85/15) to give 105 mg of the expected product 3,4,5-trimethoxy-benzoate of (S) 2 - [( 1-isobutyryloxyethoxycarbonyl) methylamino] -2-phenyl-n-butyl as a colorless oil (yield = 15%).

1H-NMR (CDCl3, 300MHz): δ (ppm) = 0.91 (m, 3H, ethyl CH3); 1.10 (m, 6H, 2 x isopropyl CH3); 2,2 (br, 2H, ethyl CH 2); 2.4 (br, 3H, CH 3 CH); 3.05 (br, 4H, CH3N + CH isopropyl); 3.89 (s, 6H, CH 3 O); 3.89 (s, 6H, CH 3 O); 3.91 (s, 3H, CH 3 O); 4.89-4.98 (br, 2H, OCH 2); 6.71 (br, 1H, OCHO); 7.17-7.39 (m, 7H, ArH).

Rf (SiO2, cyclohexane / ethyl acetate, 6/4): 0.9 MS (ES +): [M + NH4] +, m / z: 549.2 Example 16 ORC056

Step 1 :

Under nitrogen, 2 g (5.4 mmol, 1.0 eq) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate are dissolved in 4 ml of dichloromethane. The mixture is cooled to 2 ° C. At this temperature, 884 μl (8.0 mmol, 1.5 eq) of α-chloroethyl chloroformate are added dropwise. The mixture is stirred at ambient temperature for 5 hours. The reaction is monitored by TLC. The dichloromethane is evaporated with nitrogen. The residue obtained as a colorless oil is used in the next step without further purification.

¹ H-NMR (CDCl _3, 300MHz): δ (ppm) = 0.94 (m, 3H, CH _3); 1.59 (m, 3H, CH ₃ ); 2.22 (m, 1H, CH ₂ diastereotope); 2.45 (m, 1H, CH ₂ diastereotope); 3.08 (br, 3H, NCH ₃ ); 3.90 (s, 3H, OCH ₃ ); 3.91 (s, 3H, OCH ₃ ); 3.92 (s, 3H, OCH ₃ ); 5.00 (br, 2H, OCH ₂ ); 6.48 (br, 1H, ClCH); 7.19-7.39 (m, 7H ₅ ArH). R _f (SiO ₂ , cyclohexane / ethyl acetate, 6/4): 0.8 Step 2:

The (S) 2 - [(1-chloro-ethoxycarbonyl) -methyl-amino] -2-phenyl-n-butyl 3,4,5-trimethoxy-benzoate obtained in the previous step is dissolved in 3 ml of N N, N-dimethylformamide. 2.0 g (8.03 mmol, 1.5 eq) of cesium (acetylamino) acetate are added. The mixture is stirred at 55 ° C overnight. The reaction is monitored by TLC.

20 ml of water are added to the mixture. The product is extracted with ethyl acetate (3 x 50 mL) and then the organic phase is washed successively with water and saturated sodium chloride solution (10 mL). The organic phases are dried over Na ₂ SO ₄ , filtered and then concentrated to dryness to restore a brown oil. The oil is purified by flash chromatography on silica gel (eluent: cyclohexane / ethyl acetate: 3/7) to give 200 mg of the expected product 3,4,5-trimethoxy-benzoate of (S) 2 - {[ 1- (2-acetylamino-acetoxy) -ethoxycarbonyl] -methyl-amino-2-phenyl-n-butyl as a brown solid (yield = 7%).

1H-NMR (CDCl 3, 300MHz): δ (ppm) = 0.81 (m, 3H, ethyl CH 3); 1.94 (s, 3H, CH3CO); 2.15 (m, 2H, ethyl CH 2); 2.35 (m, 3H, CH 3 CH); 3.0 (br, 3H, CH3N); 3.90 (m, 9H, OCH3); 4.80 (m, 2H, OCH 2); 5.95 (br, 2H, CH 2 N); 6.65 (br, 1H, OCHO); 7.10-7.30 (m, 7H, ArH).

Rf (SiO2, Cyclohexane / ethyl acetate, 3/7): 0.2 [M + NH4] +, m / z: 578.2

The products of general formula (I) may be administered orally, parenterally, perlingually, rectally, aerosolized or in topical form.

The present invention also relates to pharmaceutical compositions comprising at least one ester derivative 2-amino-2-phenyl-alkanol of general formula (I) and / or their salts, when they exist, in ^the pure state or in ^the form of combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants. These compositions may be presented in the form of solid compositions, in particular in the form of tablets, coated tablets, pills, capsules, powders to be dissolved or suspended, or granules, or in the form of liquid compositions, such as solutions. or injectable suspensions, oral solutions or suspensions, syrups, emulsions, elixirs containing inert diluents such as water or paraffin oil or in the form of suppositories, creams, ointments and lotions or still in the form of spray compositions. These pharmaceutical forms are prepared according to the usual methods.

In the solid compositions for oral administration, the active product according to the invention is mixed with one or more inert diluents or adjuvants, such as, for example, sucrose, lactose, starch or its derivatives, microcrystalline cellulose, colloidal silica, povidone, talc, gum arabic.

These compositions may comprise substances other than diluents, for example a lubricant such as magnesium stearate or a coating intended for controlled release.

Liquid compositions for oral administration may include aqueous or non-aqueous vehicles such as diluents and may also include other substances such as wetting, sweetening or flavoring products. The non-aqueous compositions may comprise fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, and soy lecithin.

The compositions which can be administered parenterally are, more particularly, compositions that can be administered intramuscularly or intravenously. The compositions for parenteral administration may be sterile solutions or emulsions. As the solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate, may be used.

These compositions may also contain adjuvants, in particular wetting agents, isotonic agents, emulsifiers, dispersants, stabilizers, and / or preservatives.

Sterilization can be done in several ways, for example using a bacteriological filter, irradiation or heating. The compositions may also be prepared as sterile solid compositions which are dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions by rectal administration are suppositories or rectal capsules, which contain in addition to the active ingredient, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols. The compositions for topical administration may for example be patches which contain, in addition to the active ingredient, compatible excipients such as silicone oil or paraffin.

The compositions may also be aerosols. For use in the form of liquid aerosols, the compositions may be stable sterile solutions or solid compositions dissolved at the time of use in pyrogen-free sterile water, in serum or other pharmaceutically acceptable carrier. For use in the form of dry aerosols intended to be directly inhaled, the active principle is finely divided and combined with a water-soluble solid diluent or carrier with a particle size of 30 to 80 μm, for example dextran, mannitol or lactose.

In human therapeutics, the doctor will determine the dosage that he considers most appropriate according to the treatment, according to the age, the weight, and other factors specific to the subject to be treated. The usual dose, variable depending on the subject treated and the condition in question, may be, for example, from 50 mg to 2 g per day for an adult, orally. The following example illustrates a composition according to the invention.

Example

An orally administrable formulation having the following composition is prepared:

(S) 2- (Chloromethoxycarbonylmethylamino) -2-phenyl-n-butyl 3,4,5-trimethoxybenzoate 100 mg lactose monohydrate, modified corn starch, hydroxypropyl methylcellulose, sodium carboxymethyl starch, tartaric acid, colloidal silica, stearate magnesium, macrogol 4000, titanium dioxide.

Claims

An ester derived from 2-amino-2-phenylalkanol of the general formula:

in which: R 1 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms in a straight or branched chain, an alkyl radical containing 2 to 4 C in a straight or branched chain substituted with hydroxy, alkoxy, alkylthio, acyloxy, amino alkylamino, dialkylamino, alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido,

R ₂ is a -CO-R radical in which R is a hydrogen atom, an alkyl radical, an aryl, heterocyclyl, benzyl or heterocyclylmethyl radical, a -CO-YR ₄ radical for which Y is a heteroatom selected from -O -, -S-, -NH-, -NaIk- for which alk is a straight or branched alkyl radical containing 1 to 4C, and R ₄ is chosen from alkyl, aryl, aralkyl or heterocyclylalkyl radicals, which may be substituted with one or several halogen atoms or hydroxy, alkyl radicals containing from 1 to 4C in straight or branched chain, alkoxy, alkylthio, acylaminoalkylthio, alkoxycarbonyl or acylamino, the alkyl radicals of which contain 1 to 4C in a straight or branched chain, or oxo, or which may be substituted by a radical R ₅ COO- in which R ₅ represents an alkyl radical optionally substituted by benzyloxycarbonylamino, acylamino or by the residue of an amino acid, or represents a heterocyclyl radical, or R ₂ is an alkyl radical containing 2 to 4C subs characterized by hydroxy, alkoxy, alkylthio, acyloxy, amino, alkylamino, dialkylamino whose alkyl parts can form with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycle optionally carrying another heteroatom selected from oxygen or nitrogen, or substituted by alkylcarbamoyloxy, alkoxycarbonylamino, ureido or alkylureido, it being understood that said substituted alkyl radical is straight or branched chain and comprises at least 2 carbon atoms between the nitrogen atom bearing R ₂ and the substituent ;

R ₃ is an alkyl radical containing 1 to 4 carbon atoms in straight or branched chain, in its R or S forms or mixtures thereof, and its pharmaceutically acceptable salts, where they exist ,.

2. An ester derived from 2-amino-2-phenylalkanol according to claim 1, characterized in that it corresponds either to the formula (Ia) corresponding to the general formula (I) for which R 1 and R ₃ are as defined in claim 1, and R ₂ in -NR ₁ R ₂ is a radical -CO-OR ₄ for which R 4 has a structure:

C (alk) -O-CO-R ₅ (X) alk being an alkyl radical containing 1 to 6 carbon atoms in straight or branched chain and R ₅ is defined as in claim 1, or characterized in that corresponds to the formula (Ia ') corresponding to the general formula (I) for which R ₃ is defined as in claim 1, and in -NRiR ₂ , R 1 is a hydrogen atom and R ₂ is a radical -CO- R as defined in claim 1.

3. An ester derived from 2-amino-2-phenylalkanol according to claim 2, characterized in that it corresponds to the general formula (Ia) for which R 1 is a hydrogen atom, an alkyl radical containing 1 to 4 carbon atoms, preferably methyl, or a 2-methoxyethyl radical and R ₂ and R ₃ are defined as in claim 2.

4. An ester derived from 2-amino-2-phenylalkanol according to claim 1, characterized in that it corresponds to formula (Ib), of general formula (I) for which R 1 and R ₃ are defined as in claim 1 and R ₂ in -NR ₁ R ₂ is a substituted alkyl radical as defined for R ₂ in claim 1.

5. A process for the preparation of a derivative according to claim 1, characterized in that a derivative of general formula is used:

in which R 1 and R ₃ are defined as above and R ' ₂ is a hydrogen atom or is defined as R ₂ in claim 1, and if appropriate, when one of R' ₂ or R 1 is the atom of hydrogen, performs the substitution of the amine of the obtained 2-amino-2-phenyl-alkanol ester, of general formula: in which R ₁ , R ' ₂ and R ₃ are defined as above,

Or, when R ' ₂ is H, and if it is desired to obtain derivatives for which R ₂ is -CO-R, by the action of a reactive derivative of the acid of general formula R-COOH (V) in which R is defined as in claim 1,

• or, when R ' ₂ is H, and if one wants to obtain derivatives for which R ₂ is -CO-YR ₄ , Y being O, S, NH or NaIk or, by action of phosgene, followed by reaction with the alcohol, the thiol or the amine of general formula:

R ₄ -YH (VI) in which R ₄ is an optionally substituted alkyl radical and, where appropriate, the alterable functional groups in the reaction are protected beforehand, or an aryl, aralkyl or heterocyclylalkyl radical, and Y is the oxygen atom or of sulfur, or an NH or NaIk radical or else by action of the halide of general formula:

R ₄ -Y-COHaI (VII) in which R ₄ is defined as in claim 1, preferably aryl or branched alkyl, Y is the oxygen or sulfur atom and HaI is a halogen atom, preferably chlorine, or else, when it is desired to obtain a radical R ₄ bearing the substitution -C (alk) -O-CO-R ₅ for which alk is defined as in claim 2 and R ₅ is defined as in the claim 1, by the action of chloroalkylchloroformate, followed by the reaction of the product obtained with an alkaline salt of the corresponding acid R ₅ COOH, or the silver salt or a quaternary ammonium salt of this acid.

Or, when R ' ₂ is H, and if it is desired to obtain derivatives for which R ₂ is substituted alkyl, or when a derivative of general formula (IV) for which R 1 is a hydrogen atom is obtained. hydrogen and R ' ₂ is defined as R ₂ in claim 1, and if it is desired to obtain a product of general formula (I) for which R ₁ is optionally substituted alkyl, by acylation with an acid halide or a reactive ester of structure:

R ₂ -CO-Z (VIIIa) or

R 1 -CO-Z (VIIIb) wherein R 1 or R ₂ are defined as above and Z is a halogen atom or the remainder of a reactive ester, followed by reduction of the amide formed to an amine.

Or else, when a derivative of general formula (IV) for which R 1 is a hydrogen atom has been obtained and R ' ₂ is defined as R ₂ in claim 1, and if it is desired to obtain a product of general formula (I) for which R 1 is alkyl, by the action of a halogen derivative of formula

R ₁ -X (IX) in which R 1 is an alkyl radical and X is a halogen atom or a sulphonic radical, in the presence of a base, and then optionally converts the product obtained into a pharmaceutically acceptable salt, when they exist .

6. A pharmaceutical composition comprising at least one product according to claim 1, in the pure form or in the form of an association with one or more compatible and pharmaceutically acceptable diluents or adjuvants.